According to a recent report by the World Health Organization, obesity has reached global epidemic proportions. In 2008, 1.5 billion adults world-wide were overweight, and of these, more than 500 million were clinically obese. Obesity, which is often caused by excessive intake of calories, also poses a major risk for type 2 diabetes, cancer, non-alcoholic fatty liver, and cardiovascular diseases.
Adipocytes are the primary components of fat tissue (Cypess et al., 2009). Two major types of fat tissue (adipocytes) exist—“white” adipose tissue (WAT) and “brown” adipose tissue (BAT). White adipocytes store chemical energy in form of triglycerides and release fatty acids as an energy source. In contrast, brown adipocytes break down fatty acids to generate body heat. An overabundance of white fat characterizes human obesity. Beige adipocytes, which are cells with intermediate phenotype between that of white and brown adipocytes, are also known (Ishibashi and Seale, 2011). Beige cells have low basal expression of UCP1 (like white adipocytes) but respond to cyclic AMP stimulation with high UCP1 expression and respiration rates (like brown adipocytes). Beige adipocytes origins are thought to be from precursor cells within white fat (Wu et al. 2012).
Functional brown adipocytes were thought, until recently, to exist only in human newborn babies, young children, certain disease states, and small mammals. Recent studies have shown that a limited number of brown or beige adipocytes are also present and functional in human adults (Cypess et al., 2009, van Marken Lichtenbelt et al., 2009; Wu et al 2012, and Virtanen et al., 2009). An intriguing observation from these studies is that thinner people have more brown adipocytes than overweight or obese people (Cypess et al., 2009). This correlation supports a long-held hypothesis that obesity might be caused by the loss of functional brown adipocytes (Himms-Hagen, 1979). Indeed, experimental increases in BAT in animals are associated with a lean and healthy phenotype (Kopecky J. et al. 1995; Himms-Hagen et al. 1994).
Mature skeletal muscle contains “satellite cells” which are adult stem cells (Charge and Rudnicki, 2004). Satellite cells undergo self-renewal and participate in the differentiation process to both repair and create new muscle fibers.
Two recent studies revealed that skeletal muscle cells and brown adipocytes, but not white adipocytes, are unexpectedly derived from the same regions of the embryonic somites (dermomyotome) (Seale et al., 2008; Lepper and Fan, 2010). Brown adipocytes and skeletal muscle cells also share common features such as high mitochondrial content and energy-expensing nature of metabolic type (Farmer, 2008). Importantly, it has been shown that cultured satellite cells can be transformed into functional brown adipocytes by overexpressing brown adipocyte-enriched transcription factors, such as Prdm16 (Seale et al. (2008), and Kajimura et al., 2009). Thus, PR domain containing 16 (Prdm16), a zinc finger transcription factor, activates the brown adipogenic program while repressing the myogenic program. Conversely, reduced expression of Prdm16 drives brown preadipocytes to undergo myogenic differentiation.
MicroRNAs (miRNAs or miRs) are conserved non-coding small RNAs, which regulate gene expression (D. P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281 (Jan. 23, 2004)). MicroRNAs bind to the 3′ untranslated regions (3′UTRs) of target mRNAs to reduce their translation and stability. More than one-third of protein-encoding mRNAs in mammalian transcriptomes are predicted to be directly regulated by microRNAs.
The epidemic of obesity demands new therapeutic options.